mGluR5 PAMs rescue cortical and behavioural defects in a mouse model of CDKL5 deficiency disorder

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a devastating rare neurodevelopmental disease without a cure, caused by mutations of the serine/threonine kinase CDKL5 highly expressed in the forebrain. CDD is characterized by early-onset seizures, severe intellectual disabilities, autistic-like traits, sensorimotor and cortical visual impairments (CVI). The lack of an effective therapeutic strategy for CDD urgently demands the identification of novel druggable targets potentially relevant for CDD pathophysiology. To this aim, we studied Class I metabotropic glutamate receptors 5 (mGluR5) because of their important role in the neuropathological signs produced by the lack of CDKL5 in-vivo, such as defective synaptogenesis, dendritic spines formation/maturation, synaptic transmission and plasticity. Importantly, mGluR5 function strictly depends on the correct expression of the postsynaptic protein Homer1bc that we previously found atypical in the cerebral cortex of Cdkl5-/y mice. In this study, we reveal that CDKL5 loss tampers with (i) the binding strength of Homer1bc-mGluR5 complexes, (ii) the synaptic localization of mGluR5 and (iii) the mGluR5-mediated enhancement of NMDA-induced neuronal responses. Importantly, we showed that the stimulation of mGluR5 activity by administering in mice specific positive-allosteric-modulators (PAMs), i.e., 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) or RO6807794, corrected the synaptic, functional and behavioral defects shown by Cdkl5-/y mice. Notably, in the visual cortex of 2 CDD patients we found changes in synaptic organization that recapitulate those of mutant CDKL5 mice, including the reduced expression of mGluR5, suggesting that these receptors represent a promising therapeutic target for CDD

Effect of the relative shift between the electron density and temperature pedestal position on the pedestal stability in JET-ILW and comparison with JET-C

The electron temperature and density pedestals tend to vary in their relative radial positions, as observed in DIII-D (Beurskens et al 2011 Phys. Plasmas 18 056120) and ASDEX Upgrade (Dunne et al 2017 Plasma Phys. Control. Fusion 59 14017). This so-called relative shift has an impact on the pedestal magnetohydrodynamic (MHD) stability and hence on the pedestal height (Osborne et al 2015 Nucl. Fusion 55 063018). The present work studies the effect of the relative shift on pedestal stability of JET ITER-like wall (JET-ILW) baseline low triangularity (\u3b4) unseeded plasmas, and similar JET-C discharges. As shown in this paper, the increase of the pedestal relative shift is correlated with the reduction of the normalized pressure gradient, therefore playing a strong role in pedestal stability. Furthermore, JET-ILW tends to have a larger relative shift compared to JET carbon wall (JET-C), suggesting a possible role of the plasma facing materials in affecting the density profile location. Experimental results are then compared with stability analysis performed in terms of the peeling-ballooning model and with pedestal predictive model EUROPED (Saarelma et al 2017 Plasma Phys. Control. Fusion). Stability analysis is consistent with the experimental findings, showing an improvement of the pedestal stability, when the relative shift is reduced. This has been ascribed mainly to the increase of the edge bootstrap current, and to minor effects related to the increase of the pedestal pressure gradient and narrowing of the pedestal pressure width. Pedestal predictive model EUROPED shows a qualitative agreement with experiment, especially for low values of the relative shift

High-Speed Machines: Typologies, Standards, and Operation under PWM Supply

This paper presents an overview of the most recent state of the art in the field of high-speed electric machines fed through high-frequency converters. This type of systems is rapidly wide spreading in aeronautical and automotive applications, as well as microturbines. Each typology has its own advantages and downsides, which are analytically presented in this paper. Some types of high-speed electric machines require high-frequency voltage supply, highly stressing the dielectric materials of the winding insulation system. For this reason, in high-speed electric drives, premature failure may occur and a reduction of the total system reliability has been observed in the past years. Such issues are comprehensively investigated in this paper

Erosion and deposition in the JET divertor during the second ITER-like wall campaign

Erosion of plasma-facing materials and successive transport and redeposition of eroded material are crucial processes determining the lifetime of plasma-facing components and the trapped tritium inventory in redeposited material layers. Erosion and deposition in the JET divertor were studied during the second JET ITER-like wall campaign ILW-2 in 2013-2014 by using a poloidal row of specially prepared divertor marker tiles including the tungsten bulk tile 5. The marker tiles were analyzed using elastic backscattering with 3-4.5 MeV incident protons and nuclear reaction analysis using 0.8-4.5 MeV 3He ions before and after the campaign. The erosion/deposition pattern observed during ILW-2 is qualitatively comparable to the first campaign ILW-1 in 2011-2012: deposits consist mainly of beryllium with 5-20 at.% of carbon and oxygen and small amounts of Ni and W. The highest deposition with deposited layer thicknesses up to 30 μm per campaign is still observed on the upper and horizontal parts of the inner divertor. Outer divertor tiles 5, 6, 7 and 8 are net W erosion areas. The observed D inventory is roughly comparable to the inventory observed during ILW-1. The results obtained during ILW-2 therefore confirm the positive results observed in ILW-1 with respect to reduced material deposition and hydrogen isotopes retention in the divertor

Comparison of the efficiency of various substrates in growing vertically aligned carbon nanotube carpets

The intensity of 9Be + p nuclear fusion reactions was experimentally studied during second harmonic (2ω CH) ion-cyclotron resonance heating (ICRH) and further analyzed during fundamental hydrogen minority ICRH of JET-ILW hydrogen and deuterium plasmas. In relatively low-density plasmas with a high ICRH power, a population of fast H+ ions was created and measured by neutral particle analyzers. Primary and secondary nuclear reaction products, due to 9Be + p interaction, were observed with fast ion loss detectors, γ-ray spectrometers and neutron flux monitors and spectrometers. The possibility of using 9Be(p, d)2α and 9Be(p, α)6Li nuclear reactions to create a population of fast alpha particles and study their behaviour in non-active stage of ITER operation is discussed in the paper